Overview of Growth Hormone Therapy

Growth hormone replacement therapy (GHRT) is a regimen for treating deficiencies in children and adults whose bodies, for one or more reasons fail to produce adequate somatropin (somatotropin, human growth hormone, hGH). This hormonal deficit contributes to poor growth and development in children, and in adults fails to maintain essential aspects of bodily form and function that are needed for a healthy life of normal duration.

The medical condition resulting from inadequate production and/or utilization of hGH is called growth hormone deficiency (GHD).^[1] Most cases are initially observed as an endocrine disorder in children that occurs equally in males and females, although males are often diagnosed more frequently.^[2][3] Because of its significant effect on growth and development as well as causing associated medical problems and reduced quality of life, childhood-onset GHD has been treated with replacement therapy for more than 30 years. In the past, hGH therapy in children affected by GHD was stopped at the time of epiphyseal closure (i.e. at final height). This focus on height originally reflected a measure of successful GH replacement therapy (GHRT) after which treatment was ended. This was done, in part because hGH was originally extracted from human cadavers making its supply fairly limited. However, with advances in technology, it became possible to clone the gene capable of producing hGH. Thereafter, the recombinant form of human growth hormone (rhGH) became available in unlimited quantities. Because of its availability for clinical application, rhGH became and is now the drug of choice, not only because of its efficacy but also because it avoids the risk of transmitting fatal, slow viral (prion-mediated) Creuzfeldt Jacob Disease which was sometimes associated with the cadaver-derived hormone.^[4] Although originally indicated for use in childhood GHD, rhGH became a licensed indication for GH-deficient adults in the United States, a number of European countries, and New Zealand in 1996. This action was taken because people who had been treated with rhGH as children and then routinely discontinued from treatment upon reaching final height, experienced higher than expected rates of medical problems as adults, beginning in their 30s and 40s. These included reduced physical, mental, and social energy, excess adipose tissue, diminished muscle mass, diminished libido, poor bone density, higher than normal cholesterol levels, and elevated rates of cardiovascular disease. Research trials soon confirmed that a few months of GH replacement therapy could improve nearly all of these parameters in GHD patients. Coincidentally, it was noticed that the same intrinsic diseases as well as maladaptive changes in form and function also occur spontaneously with advancing age.^[5]

The progressive age-associated decrements in function of the GH neuroendocrine axis are collectively referred to as the somatopause. The term represents cessation of optimal secretion of somatotropin (hGH) which is analogous to declining production of reproductive hormones during the menopause and andropause in women and men, respectively. However, there are pathophysiological differences in childhood-onset and adult-onset GHD (AGHD) when compared with progressive, age-related GHD. Initial investigations into the causes of adult onset GHD showed them to result from damage to the pituitary gland due to tumors, surgery or radiotherapy that disrupted function of the GH neuroendocrine axis.^[6][7] Since age-related GHD is not associated with the strict and exclusive acceptance of these originally defined, causal criteria for adult-onset GHD, nor is aging generally considered a “disease”, there was and continues to be reticence to diagnose GHD in the obese and in the elderly.^[8][9][10] Thus at first, little attention was paid to the fact that as the body ages, progressive dysfunction of the GH neuroendocrine system results in clinical symptoms similar to those associated with factors originally recognized as causal for GHD.

For these reasons, administration of rhGH which is the accepted treatment for GHD, has not been permitted for use in aging by regulatory guidelines promulgated by the FDA. As a result, rhGH supplementation is not approved for medical treatment of the pathophysiologic, age-related decline in GH/IGF secretion, despite the clinical similarities with classically defined, adult-onset GHD. If used at all, lower doses are recommended in the elderly to reduce the incidence of side effects and maintain age-dependent normal levels of IGF-1. This is a confusing recommendation for the following reason. IGF-1 levels in normal young adults is higher than those in GHD adults. However, serum IGF-1 values in both groups are indistinguishable by the age of 40. Nonetheless, the declining values in “normal” aging people are not considered to be diagnostic criteria for GHD or GH insufficiency worthy of treatment with rhGH. Instead the range of laboratory reference values are shifted downward to reflect those in human subjects as they advance in age. Surprisingly, this is a unique practice which is not done for serum values of any other hormones. Nonetheless, it restricts in part, diagnosis of idiopathic GHD and treatment with rhGH to those under 40, and thereby requires different treatments for medical issues related to age-associated, GH insufficiency. To differentiate between classically defined adult-onset and age-related GHD associated with the somatopause, the latter is often called growth hormone insufficiency (GHI). Thus, because of the similarities between GHD resulting from trauma, disease or radiation from effects of aging that occur during middle and later stages of life, endocrine therapies for treating the latter condition have been sought over the past two decades.^[11] In fact many years of off-label use of sermorelin, a GH secretagogue, has improved the life and health of many suffering from progressively degenerative conditions of aging.

Somatopause

Many of the body’s systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline with age. Loss of muscle mass, or sarcopenia, and the accompanying reduction in strength increases the risk of falls and their complications, and for many individuals the associated loss of physical, functional capacity leads to increasing difficulty in living independently. Complaints of poor sleep are common in older populations. Insomnia reduces quality of life and is often a factor in decisions to seek health care. Sleep complaints often lead to overmedication and sedation of the elderly, with the numerous potential attendant problems, including increased morbidity and mortality. Finally, cognition also declines with advancing age, particularly those cognitive functions that involve novel problem solving and psychomotor processing speed, with its own related impact on the older individual’s ability to function independently.^[12] Aging in both sexes is accompanied by profound decreases in GH output and in plasma IGF-I concentrations. This effect is separate from the alterations in body mass index that accompany the normal aging process. Attenuation of GH output associated with aging is related by inference to reduced GH-releasing hormone (GHRH) production, pulse amplitude as well as increased somatostatin (SRIF).^[13][14][15]

GH secretion rates decline exponentially from a peak of about 150 μg/kg/day during puberty to about 25 μg/kg/day by age 55.^[14] During this process there is a reduction in GH pulse amplitude, but little change in GH pulse frequency.^[16] There is a particularly marked decline in sleep-related GH secretion, resulting in loss of the nocturnal pulsatile GH secretion seen in younger individuals and lack of a clear night-day GH rhythm.^[17][18] The decline in GH production parallels the age-related decline in body mass index and is associated with alterations in body composition, hormonal status, and functional capacity that mimic the changes seen in AGHD or partial hypogonadism.^[19] In addition to deteriorating memory and cognitive function, the changes in body composition that are most pronounced in normal aging include a reduction in bone density and in muscle mass and strength, an increase in body fat, and adverse changes in lipoprotein profiles.^[20][21] While the aging pituitary remains responsive to GH, GHRH, and GH secretagogues, it is less responsive to stimuli such as exercise. This decline in GH production is initially clinically silent, but may contribute over time to sarcopenia and frailty. Since GH secretion declines progressively and markedly with aging, and many age-related changes resemble those of partial adult-onset GHD, stimulating production and secretion of endogenous GH with GH-releasing hormone (GHRH) or its analog Sermorelin, a GH secretagogue, could confer benefits in normal aging similar to those observed in AGHD. In particular, such treatment could reduce the loss of muscle mass, strength, and exercise capacity that leads to frailty; thereby prolonging the ability to live independently.

Growth Hormone Secretagogues

Growth hormone secretagogues (GSH) are a class of molecules that stimulate the secretion of GH from the pituitary gland. They include agonists of the hypothalamic and pituitary ghrelin receptors (GHRPs, ipamorelin, hexarelin, etc.), and those of the pituitary GHRH receptor such as Sermorelin.

Sermorelin is a synthetic (man-made) version of naturally occurring GHRH that is produced in the brain and can be used clinically to stimulate release of growth hormone (GH) from the pituitary gland.^[22] Growth hormone is necessary for growth in children and is important in adults to maintain metabolic and physiologic functions that are necessary for good health and quality of life. Thus, Sermorelin can be effective in cases of GH insufficiency and thereby sustain essential bodily functions throughout life.

Clinical Applications

Some uses for Sermorelin include: Diagnosis of growth hormone deficiency/insufficiency (GHD), treatment of children with idiopathic growth hormone deficiency, management of adult-onset growth hormone deficiency/insufficiency and other conditions requiring GH replacement therapy (GHRT), regeneration of pituitary function and delay its functional decline during aging. ^{[23][24][25][26]}

General Information

After Roger Guillemin and Andrew Schally were awarded the 1977 Nobel Prize in Medicine for their work on neuroendocrine releasing factors, the precise chemical structure of GHRH, a 44 amino acid peptide, was determined using tissue from human pancreatic tumors that caused acromegaly, a disease resulting from excess secretion of GH.^[27] The following year, Wehrenberg and Ling sought to determine which part of the molecule was essential for its pituitary stimulating action.^[28] By eliminating individual amino acids and then testing the remaining peptide fragments, they found that only the first 29 amino acids are needed for stimulating pituitary production and secretion of HGH. Consequently, this fragment of the native molecule, commonly known as Sermorelin is often used to treat GH deficient states in children and adults

Chemically, sermorelin is known as growth hormone releasing factor (GRF) or growth hormone releasing hormone (GRH)1-29 NH₂ indicating that the amino terminus is at position 29. However, the molecule is not used clinically as the free base, but rather as the acetic acid salt, i.e. as sermorelin acetate. The free base of sermorelin has the empirical formula C₁₄₉H₂₄₆N₄₄O₄₂S and a molecular weight of 3,358 daltons.^[29] Sermorelin acetate is a sterile, non-pyrogenic, lyophilized powder intended for subcutaneous injection after reconstitution with Bacteriostatic Water for Injection and should be stored at between 36 and 46° F (2 and 8° C). Taxonomically, sermorelin is listed as an organic compound (kingdom), an organic acid (superclass), a carboxylic acid (class), amino acid/peptide analogue (subclass), and as a peptide (direct parent).^[30]

Sermorelin is the most widely used member of the GHRH analogue drug class. It can significantly promote the synthesis and release of growth hormone (GH) from cells in the pituitary gland, improving the serum concentrations of GH and subsequently insulin-like growth factor 1 (IGF-1) in animals and humans.^[31][32] It is able to influence the concert of hormonal signals that affect GH secretion from the anterior pituitary including GHRH, somatostatin, and insulin like growth factor (IGF) and others. The positive and negative opposing regulation of growth hormone by GHRH and somatostatin, respectively, creates a rhythmic-circadian pattern of GH secretion.^[33] Thus, modification of both pulse amplitude and frequency of GH secretion results from Sermorelin administration.^[34] After sermorelin stimulates the release of GH from the pituitary gland, it increases synthesis of IGF-1 in the liver and peripheral tissues.^[34]

Sermorelin acts on the growth hormone releasing hormone receptor (GHRHr) in the pituitary to regulate cellular activities. GHRHr is the natural receptor for the endogenous hormone, GHRH, and for sermorelin. This receptor regulates growth hormone release directly by stimulation and indirectly by a feedback relationships with somatostatin.^[35]

Sermorelin is readily degraded after reaching the bloodstream, having a biological half-life of approximately 10-20 min.^[36] Due to the biological half-life and bioavailability of Sermorelin, administration for growth in childhood GHD must occur periodically several times a day as subcutaneous-injections.^[37] However, single daily dosing is sufficient to treat most cases of adult-onset GH insufficiency. Three (3) mcg/kg subcutaneous-injections of Sermorelin have been reported to simulate a naturally occurring GHRH mediated GH release responses.^[38]

In addition to increasing production and secretion GHRH also affects sleep patterns by increasing the amount of slow wave sleep (SWS) while augmenting sleep-related GH secretion and reducing cortisol secretion.^[39]

To exert all its beneficial effects, Sermorelin requires a functioning pituitary and a host of peripheral tissues.^[40][41] This is due to the reliance on endogenous receptors controlling hormone secreting glands and tissues. More precisely, functioning growth hormone releasing hormone receptors (GHRHr) are required on somatotrophs in a functioning anterior pituitary.^[40]

Indications

Because of Sermorelin’s ability to bind receptors on somatotrophs, the pituitary cells that produce and secrete GH, sermorelin has several clinical indications and applications related to GHRH/GH insufficiency.^[42] For example it is officially indicated and approved for diagnostic evaluation of pituitary function and also for treatment of delayed or inadequate growth in children. It also can be used to oppose maladaptive changes in body composition such as reduced lean body mass (muscle), increased total and visceral fat, and decreased bone mass resulting from low or inadequate concentrations of serum GH and insulin-like growth factor-1 (IGF-1).

Data from research and clinical studies have demonstrated sermorelin’s multifaceted properties, some of which include:

• Peak increases in hGH followed administration of GHRH analogs after 15 or 30 min. An increase in the integrated plasma growth hormone (GH) response was observed at each dose.^[43]
• Quality of life parameters including general well-being (P < 0.05) and libido (P < 0.01) significantly improved in men receiving sermorelin therapy.^[44]
• Youthful concentrations and patterns of serum hGH were restored in older persons by daily injections of GRF (sermorelin).^[45]
• Body composition improved after regular administration of GRF for 90 days resulting in increased muscle mass, increased total body water and decreased visceral fat.^[46]
• Quality of sleep improved as indicated by extended Stage IV and Slow Wave Sleep in men.^[47]

Symptoms and Diagnosis of Adult Growth Hormone Deficiency

Adults with inadequate concentrations of serum GH can have a variety of signs and symptoms, some of which include abnormal body composition, reduced fluid volume, diminished strength, physical energy and stamina, lack of motivation, lethargy, lability etc. Symptoms of growth hormone deficiency also depend on age, and often those meeting the classic definition of adult onset GHD can have different symptoms than a child similarly diagnosed. However, those with adult-onset GHD that are causally unrelated to aging have similar clinical symptoms as those that occur progressively in incidence and severity with advancing age.^[48]

Not everyone with growth hormone deficiency/insufficiency will have the same symptoms. Some people will only have one or two while others can have multiple symptoms. Fortunately, certain tests and exams can help physicians to make an appropriate diagnosis. Exams and tests used to diagnose growth hormone deficiency are the same no matter the patient’s age.

Diagnosing growth hormone deficiency typically starts with a physical exam. The physician checks weight, height, and body proportions. Other than a physical exam, there are many other tests and exams used to make a growth hormone deficiency diagnosis.

With respect to diagnosis of adult GHD of classical etiology, guidelines state that “adult patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies are considered appropriate for acquired GHD” and that “idiopathic GHD as which occurs during aging requires stringent criteria to make the diagnosis. The reason for this restriction is that as previously described, the age-related decline in function of the GH neuroendocrine axis is accepted as being a “normal” part of aging, even though it is progressively detrimental to many aspects of body function. Thus, due to the nature of the original diagnostic criteria for GHD, and the reticence to consider aging a “disease” per se, even though disease risk, incidence and severity can be attributed at least in part to declining activity of the GH neuroendcrine axis, the criteria for determining if secretagogue therapy is indicated as an intervention in aging, are less stringent than those promulgated by Endocrine Society guidelines.^[11]

Some or all of the following tests can be used to diagnose age related GH insufficiency, since everyone will be so affected over the course of their lives. Such diagnostic testing may be used to determine the degree to which replacement therapy is indicated, i.e., for dosing determinations. Tests include:

Blood Tests for Growth Hormone Deficiency

• Binding protein level (IGF-I and IGFBP-3) blood tests to determine whether or not the problem is caused by the pituitary gland
• Blood tests to measure the amount of growth hormone levels in the blood
• Blood tests to measure other levels of hormones the pituitary gland produces
• GHRH (Sermorelin)-arginine provocative test
• Other GH provocative stimulation tests
• Insulin tolerance test

Other Exams/Tests to Diagnose Age-unrelated Severe Growth Hormone Deficiency

In addition to blood tests, a physician may perform some additional exams and tests to help diagnose growth hormone deficiency. These may include:

• Dual-energy x-ray absorptiometry (DXA) scan to measure bone density.
• Brain MRI to examine the pituitary gland and hypothalamus.
• Hand x-rays (typically of the left hand) to examine the shape and size of bones which change as a person grows and ages. Bone abnormalities can be observed with x-ray examination.
• X-rays of the head can show any problems with the bone growth.

If an individual experiences signs and symptoms of GHD or GHI, he/she should talk to a doctor immediately so as to perform exams and tests that assist in making an accurate endocrine analysis and diagnosis.

Treatment of Growth Hormone Deficiency

While aging is not a disease, it results in significantly maladaptive changes in body composition and function which affect the individual and the community at large. While aging is associated with a milder form of adult GHD, GH replacement with secretagogues such as Sermorelin has met with success. Once daily injections can stimulate increases in GH and IGF-I at least to the lower part of the young adult normal range.^[49] Because peptides like Sermorelin are readily destroyed by enzymes in the digestive tract, subcutaneous (sc) or intravenous (iv) injections are the only way to administer the molecule. Since iv injections are impractical for most people, the sc route is commonly used to administer doses of Sermorelin ranging between 0.2 – 1.0 mg per day. The most commonly used dosage is 0.5 mg daily. In a University of Washington study consisting of 6 months treatment with daily bedtime subcutaneous injections of Sermorelin, alone or in combination with supervised exercise conditioning, IGF-I levels rose approximately 35%. As with GH, subjects showed an increase in lean body mass and a decrease in body fat (particularly abdominal visceral fat).^[50][51] Such changes indicate that regular GHRT with Sermorelin can resist changes in body composition underlying sarcopenia and frailty that lead to loss of independence. Thus, since the aging pituitary remains responsive to GH and GHS, it is reasonable that stimulation with Sermorelin is indicated in aging.^[52] While elders are more sensitive to GH, and thus more susceptible to the side effects of replacement with rhGH, stimulating production and secretion of endogenous GH with Sermorelin offers the advantage of a more physiological approach to increasing GH pulsatility while reducing risk for side effects.